We are attempting the chemical synthesis of a series of corticosteroid conjugates of nucleoside antitumor agents linked through a phosphodiester bond in an effort to improve their therapeutic index in the treatment of malignant tumors. The steroids include cortisol, cortisone, corticosterone, 11-deoxycorticosterone, cortexolone, fludrocortisone, prednisolone, prednisone, 6 alpha-methylprednisolone and dexamethasone. The nucleosides include 1-beta-D-arabinofuranosylcytosine (ara-C), 9-beta-D-arabinofuranosyladenine (ara-A), 5-fluorodeoxyuridine, 6-mercaptopurine riboside, tubercidin and 5-azacytidine. The conjugates will be tested for preliminary antitumor screening against L1210 lymphoid leukemia in mice and against cultured human leukemia-lymphoma cell lines. We have synthesized 10 ara-C conjugates and significant properties found for most of these conjugates include: 1) superior antitumor activity and reduced toxicity to those of ara-C alone and in combination with steroid, 2) resistant to hydrolysis by cytidine deaminase, 3) relatively slow rate of enzymatic degradation in plasma and service as a prodrug of ara-C or ara-CMP, 4) release of cytotoxic ara-CMP by enzymatic hydrolysis and 5) water solubility. We are now synthesizing a series of the corticosteroid conjugates of ara-A and 5-fluorodeoxyuridine and evaluating further the more potent ara-C conjugates in animal tumor models.